Impact of Pharmacogenetics and Therapeutic Drug Monitoring on Optimizing Voriconazole Dosing in Pediatric Patients Undergoing Hematopoietic Cell Transplantation

Background: Invasive fungal infections are a significant cause of morbidity and mortality in recipients of hematopoietic cell transplantation (HCT), warranting antifungal prophylaxis as a standard of care. A number of options are available for prophylaxis, but none have been found to be ideal. Due to its broad spectrum of activity and multiple dosage forms, voriconazole remains one of the commonly used agents in this setting. It's well known that there is wide inter and intra-patient variability in voriconazole levels. Additionally, these levels are affected by a common CYP450 polymorphism, CYP450-2C19. The aim of our pilot study was to determine effects of therapeutic drug monitoring (TDM)and genotyping in achieving desired voriconazole levels for antifungal prophylaxis in the post HCT period. Methods:  All patients undergoing HCT at Cincinnati Children's Hospital Medical Center who received voriconazole between February 2012 and September 2012 were prospectively followed. Voriconazole concentrations were drawn weekly and adjusted until between 1 mg/L and 5.5 mg/L. Mutational analyses of the most common mutation CYP2C19 *2 were performed on all patients to determine their genotype.  All patients were monitored for common side effects of voriconazole. Results: Twenty-five patients received voriconazole as anti-fungal prophylaxis for a median of 49 days (range 15-196).  In patients with a wild type genotype the median time to therapeutic level was 30 days, for heterozygotes 47 days and 11 days for patients with variant genotype.  Time and dose required to reach adequate levels showed a trend towards correlation with CYP2C19 genotyping (Fig 1).  Voriconazole levels showed larger inter-patient variability in wild-type patients (Fig 1). Five patients had elevations three times the upper limit of normal, 1 was discontinued from voriconazole therapy. Two patients had levels  >5.5 mg/L; 1 showed clinical adverse effects. Conclusions: Our pilot study demonstrates the importance of rigorous TDM and potential utilization of CYP2C19 genotyping in selecting appropriate voriconazole dosing for patients. Despite a small number of patients, it appears that traditional voriconazole dosing of 4 mg/kg/dose every 12 hours may not be sufficient to achieve levels appropriate for prophylaxis for the majority of patients in the population, leaving such patients susceptible to fungal infections during their post HCT course, something that we plan to address in our future studies using genotype specific initial dosing.